The present invention relates to the treatment of human melanoma, basal and squamous cell skin cancer, and a variety of other skin tumors and skin diseases. More particularly, the present invention relates to unit dose packaging of a zinc chloride mixture and used in a dosage specific applicator for the treatment of these skin diseases.
Melanoma is a potentially fatal form of skin cancer, usually appearing as a black or dark brown mole. The conventional treatment of cutaneous melanoma has been excision with a deep and wide margin of normal appearing tissue surrounding the tumor depending on the depth and thickness of the cancerous mole. However, microscopic satellite sites potentially occurring in the otherwise normal appearing skin surrounding the melanoma may be disturbed, and host resistance may be reduced following the excision of the melanoma. A decrease in host resistance may result in the appearance of cancer in distant sites of the body (metastases). (Smolle, J. et al, Does Surgical Removal of Primary Melanoma Trigger Growth of Occult Metastases? An Analytical Epidemiological Approach. Dermatologic Surgery, November, 1997). Cancer metastases can cause death of the patient. Although it is common to excise a margin of tissue surrounding the tumor, it is well known that increasing the size of the surgical margin to greater and greater extent does not affect survival rate.
Adjuvant therapy has been recommended for melanoma patients in whom clinical and histopathological parameters indicate a high risk of relapse. Interferon alpha 2B has been approved by the United States Food and Drug Administration for treatment of such high-risk melanomas. However, the survival from high-risk melanomas remains poor, and additional modalities are needed. Clinical evidence shows that the pre-surgical application of zinc chloride paste improves the prognosis of melanoma.
Zinc chloride was discovered by Sir Humphry Davy of Bristol, United Kingdom, in 1815. It was used for the treatment of cancer by Canquoin of Paris and by Bougard of Brussels in the early part of the nineteenth century. Zinc chloride is a very potent chemical which deeply penetrates and kills tissue.
While a research assistant in the department of zoology at the University of Wisconsin, Dr. Frederic E. Mohs, founder of the American College of Mohs Micrographic Surgery and Cutaneous Oncology, observed that the injection of zinc chloride into cancerous tissue not only caused tissue necrosis (cell death), but, additionally, the microscopic structure of the killed tissue was retained as if the tissue had been excised and immersed in a fixative, or histologically preserving solution. Dr. Mohs developed an anti-skin cancer paste containing zinc chloride and the escharotic bloodroot plant, Sanguinaria canadensis. The formula is as follows: Stibnite (alpha, beta-Diphenylethylene 80-mesh sieve), 40 g; Sanguinaria canadensis, 10 g; and zinc chloride, saturated solution, 34.5 mL (zinc chloride 45% by weight).
Since 1941, Dr. Mohs has published a textbook and numerous articles on the successful treatment of skin cancer and melanoma using this zinc chloride paste. Dr. Mohs referred to the paste as xe2x80x9czinc chloride fixative pastexe2x80x9d and the surgery as xe2x80x9cchemosurgeryxe2x80x9d or xe2x80x9cfixed-tissue micrographic surgeryxe2x80x9d. For the treatment of melanoma, Mohs utilized a layer by layer excision technique in addition to in situ fixation of the tumorous tissue with zinc chloride fixative paste. In fixed-tissue surgery, a clinically apparent melanoma is first treated with zinc chloride fixative paste prior to any biopsy or debulking procedure. The next day, a layer of fixed tissue is excised and frozen histologic sections are made for microscopic examination to confirm the clinical diagnosis of melanoma. The melanoma is then excised layer-by-layer, with each successive layer first fixed in situ, then conservatively removed for microscopic scanning of the entire undersurface utilizing frozen histologic sections cut horizontally from the bottom of the excised specimens. The edges of the specimens are color coded by the application of dyes for precise orientation as the sections are scanned under the microscope. The zinc chloride paste is reapplied as necessary until a melanoma-free plane has been reached. An extra margin of surrounding tissue is then removed by zinc chloride fixed-tissue surgery to encompass satellite deposits that may be present in the surrounding skin lymphatics.
In 1977, Mohs published data on 103 consecutive patients with mainly advanced melanomas treated with zinc chloride fixative paste (64% Clark""s level V lesions, 20% regional lymph node involvement). The 5-year cure rate was compared with a series of melanomas treated conventionally by surgical excision alone at the Massachusetts General Hospital, and stratified by Clark""s level of invasion. In the Clark""s melanoma classification system there are five levels. Clark""s I being the most superficial and V being the deepest invasion of the skin and penetration into fatty tissue under the skin. Both studies were completed in 1968. In the conventional surgery series, all the melanomas were primary tumors without regional lymph node metastases, and the incidence of level V invasion was only one-sixth that of the zinc chloride fixative cases. Despite a 20% incidence of nodal metastases and a six times greater incidence of level V melanomas in the fixed tissue series, a significant (p=0.003) one and a half times improvement in five year survival was achieved using zinc chloride fixative paste. (Mohs, FE: Chemosurgery for melanoma. Arch Dermatol 133: 285-291,1977; Brooks, N A: Fixed-tissue micrographic surgery in the treatment of cutaneous melanoma, J. Dermatol Surg. Oncol. 1992; 18: 999-1000.)
Similar results have been found with the common skin cancers, basal cell and squamous cell carcinoma. In 1986, Dr. Almeida Goncalves and Dr. Ricardo Azevedo published their experience using a zinc chloride paste with a group of patients which consisted of 179 basal cell carcinomas and 33 squamous cell carcinomas of varying diameters. All patients had more than five years follow-up and no tumor persistence or recurrence was observed. (Goncalves J C A, Chemosurgery without systematized microscopic control for malignant skin tumorsxe2x80x94A new simplified technique. Skin Cancer, 1986; 1: 137-150). This study continued until 400 basal cell and squamous cell skin cancers had been treated. Only one persistence had occurred resulting in a cure rate of 99.7%, which is much higher than the reported cure rate for curettage and desiccation, the most commonly used method for the treatment of basal and squamous cell skin cancer (Goncalves, J C A and Azevedo, R B R. An attempt at reducing pain in cancer patients treated by chemosurgery without systemized microscopic control. Skin Cancer, 1998; 13: 145-161.Salasche, S J. Status of curettage and desiccation in the treatment of primary basal cell carcinoma. J American Acad of Dermatology, 1984; vol 10: 285-287).
While the use of zinc chloride chemosurgery has been shown to produce remarkable life-saving results, these treatments have not been grasped by the medical community. This has been due, in part, to the lack of understanding of the manner in which zinc chloride prevents relapse in cancer and increases survival rates, the difficulty in following the Mohs procedure, and the potency and instability of zinc chloride pastes. A detailed discussion of why these treatments have been overlooked and underestimated follows.
The Mohs Technique is Difficult to Perform
The Mohs method is a laborious and time consuming process, requiring the repetitive examination of multiple layers of zinc chloride fixed tissue. Furthermore, Mohs taught of the use of dressings which are complicated and difficult to apply for the application of zinc chloride paste to the skin. In the Mohs"" dressing technique, first a layer of dry cotton is applied over the zinc chloride paste to help hold it in place on the skin, then a gauze-backed, petrolatum spread cotton dressing is overlapped to make an air-tight closure. This in turn is fastened securely with Micropore paper tape. (Mohs F E, Mohs Chemosurgery Microscopically Controlled Surgery for Skin Cancer. Charles C. Thomas 1978; p 14) The Mohs"" dressing is messy and difficult to apply. Unless properly applied, the zinc chloride paste can leak out beyond the limits of the intended application.
The Rationale for using Zinc Chloride Paste has been Poorly Understood
Attempts have been made to simplify the original fixed-tissue technique based on a misunderstanding of how zinc chloride paste works in the cure of melanoma. A method known as the hybrid fixed-tissue technique was investigated. It involves excising melanomas by fresh tissue surgery and then treating the wound base with zinc chloride fixative paste in order to kill tissue and reduce the likelihood of disturbing microsatellites. In the hybrid fixed-tissue technique, the melanoma is excised without any fixation of the tumor. A melanoma tumor registry maintained by Dr. Stephen Snow, at the University of Wisconsin, Madison, compared 113 cases treated with the hybrid fixed-tissue technique (fresh tissue excision followed by fixative paste to the wound) with 61 cases treated by Mohs"" fresh tissue technique without zinc chloride. No difference in five year survival for thin and intermediate thickness melanoma was determined, putting in question the efficacy of the hybrid method. (Snow, S N, et al: Cutaneous malignant melanoma treated by Mohs surgery. Dermatol Surg. 23: 1055-1060, 1997).
The inventor initiated and helped direct a murine melanoma experiment in which a key vaccine-like property of zinc chloride paste was discovered. (Brooks, Kalish, Siegal, et al., Experimental rationale for treatment of high-risk human melanoma with zinc chloride fixative paste. Dermatologic Surgery, September, 1998, Vol 24: 1021-1025). In the experiment two murine melanoma lines were used: (1) the immunogenic K1735p melanoma and (2) the poorly immunogenic B16-F1 melanoma as a control. Mice were injected intradermally with melanoma cells, and the subsequent tumors were treated either by excision or zinc chloride paste followed by excision. After a one week rest, the mice were challenged at a different site with a second injection of the same melanoma cell line, and tumor appearance at the second site was monitored. Mice with K1735p melanoma treated with zinc chloride paste had a significant reduction in tumor development at the second challenge site relative to excision alone. Similar treatment of the poorly immunogenic B16-F1 melanoma did not result in resistance to tumor challenge relative to excision alone.
It was concluded that the zinc chloride paste acted as an immune adjuvant, inducing specific host cell mediated resistance to the immunogenic K1735p melanoma. Based upon a comparison of these results with the hybrid technique test results obtained by Dr. Snow, the survival benefit of zinc chloride fixation is related to not only the actual killing of the cells by the zinc chloride paste, but also to an immunologic adjuvant effect requiring the presence of melanoma cells and fixation of the tumor. By removing the tumor first, Dr. Snow did not get the immunologic reaction necessary to establish a melanoma immunity. Although only tested with melanoma, it is believed that similar immunologic effects are obtained with other forms of skin cancer and abnormal skin growths.
Zinc Chloride Pastes are not Stable
Zinc chloride is highly deliquescent and following manufacture the paste can become excessively liquefied in humid conditions or dry to a hardened mass during dry conditions, making the preparation ineffective. When zinc chloride is stored in a large jar in hot, humid weather the paste can draw in excess moisture and become too watery and runny to be useful. The jar of fixative often must be kept in a calcium chloride desiccator during the moist summer months. Conversely, dry atmosphere produced by heating in winter can cause the paste to dry and harden into an ineffective mass. (Mohs F E, Mohs Chemosurgery Microscopically Controlled Surgery for Skin Cancer. Charles C. Thomas 1978; p.13) Modern medical practitioners are often unwilling to spend the time required to stabilize the paste before using.
The Vast Majority of Modern Medical Practitioners are Unaware of the Proper Dosage of Zinc Chloride Paste Required in the Treatment of Melanoma, Skin Cancer and other Skin Diseases.
Zinc chloride is an extremely potent and deeply penetrating agent. The proper dose varies widely depending on the size, depth of invasion, type and location of the tumor. An improper dosage can result in a deep ulcerated wound requiring months to heal. Precise dose is necessary yet zinc chloride paste has never been available in specific dosed packages.
Accordingly, what is needed is a technique which effectively simplifies the Mohs original technique. What is also needed is an improved method of applying, administering, storing and dosing zinc chloride mixtures and/or zinc chloride pastes in the treatment of melanoma and other skin diseases. The present invention fulfills these needs and provides other related advantages.
The present invention resides in a medicinal zinc chloride mixture used in treating skin diseases, unit dose packaging, an applicator for the zinc chloride mixture, and a method of using the zinc chloride mixture to treat cancer and other skin diseases.
The zinc chloride mixture generally comprises zinc chloride, a granular matrix and sanguinaria canadensis. The preferred mixture comprises, in a saturated zinc chloride 34.5 mL solution, 45% concentration zinc chloride by weight, 40 grams of stibnite, 10 grams of sanguinaria canadensis. 
In treating a skin tumor the first step is to visually examine the abnormal skin growth. If cancer is suspected, a biopsy may be performed to determine with certainty that the abnormal growth is in fact cancerous. A skin penetration enhancing agent such as a keratolytic acid is then placed on the lesion followed by the zinc chloride mixture. Eighteen to twenty-four hours is allowed for the complete penetration of the zinc chloride. The site is subsequently inspected to determine clearance of the abnormal skin growth. If the lesion is cured, no further treatment is undertaken. If not, the process is repeated until the lesion is cured. The wound is allowed to heal spontaneously by second intention. The inspection step may include performing a biopsy to determine the clearance of a cancerous growth.
When treating plantar warts, after examining and diagnosing the lesions, the individual warts are pared with a surgical blade to remove an outer dead keratin layer. Keratolytic acid and then zinc chloride are applied to the wart. The site is later observed for healing and the process is repeated after approximately three weeks if the wart is not cured. If the lesion is cured, there is no further treatment.
In treating basal and squamous cell carcinomas, the lesion site is first visually observed, a clinical diagnosis made, and photographs may be taken. A fresh tissue biopsy of the suspected cancer may be performed, and if the lesion is benign, there is no further treatment. If the lesion is determined to be malignant, a keratolytic acid, such as trichloracetic acid, followed by the zinc chloride mixture is applied to the judged area of malignant involvement. Since zinc chloride paste preserves histology a tumor fragment may be biopsied without bleeding or pain approximately 24 hours after the application of zinc chloride.
Over time, the treated area of basal and squamous cell carcinoma becomes gray and necrotic with surrounding inflammation. After one to two weeks, the tumor sloughs off spontaneously or is easily removed with a forceps. The resulting ulcer is examined for a clean, smooth surface and normal appearing edges without evidence of residual tumor. If the tumor persists, the process is repeated until the tumor is eliminated. The wound is then allowed to heal by second intention. The skin cancer site is observed intermittently over a five year period for any evidence of local recurrence.
Treatment of melanomas also involves visually examining and diagnosing the skin site, as well as the possibility of taking photographs. A fresh tissue biopsy is taken from the thickest part of the tumor utilizing a 3.5 mm to 4.0 mm punch biopsy instrument. If the lesion is found to be benign, no further treatment is given. However, if the biopsy confirms melanoma, a keratolytic acid, such as trichloracetic acid, followed by the zinc chloride mixture is applied to the remaining melanomatous tumor and surrounding margin of normal appearing skin. The margin may vary from 6 mm to 1.5 cm depending on the size and thickness of the tumor.
The following day, a conventional surgical excision is performed on the tumor with a deep and wide margin of previously killed surrounding tissue. The excision is performed within 1 mm to 2 mm of the outer edge of the zinc chloride fixed tissue. Zinc chloride is applied to the excisional surface immediately following surgery. The 1 mm to 2 mm thin necrotic wall remains in place to provoke a surrounding inflammation.
Conventional microscopic examination of the excised tissue using traditional permanent histologic sections cut perpendicular to the skin in the vertical plane is conducted. Dyes may be applied to the edges of the excised tissue for precise tumor orientation. The tissue is examined microscopically to determine clearance of the melanomatous tumor to the deep and side margins. If the side or deep margins show inadequate microscopic tumoral clearance, the application of the zinc chloride mixture is repeated until adequate margins are achieved. After one to two weeks, the necrotic thin wall tissue remaining in the ulcer sloughs off or is easily removed with forceps. The wound heals spontaneously by second intention.
The zinc chloride unit dose packaged mixture is stored in a humectantly sealed container which maintains the stability of the paste. A dose specific single use quantity of zinc chloride mixture may be applied to the skin from the container. The mixture may be held in place with a transdermal applicator or alternately, the mixture may be in a humectantly sealed, multi-layered, flexible transdermal applicator which is positioned directly on the skin growth site. The applicator allows specific dosing and maintains the physical properties of the mixture.
The transdermal applicator may contain special pharmacologically active additives and/or skin penetration chemical enhancers (e.g. keratolytic agents and/or acids), mixed with zinc chloride mixture. Alternatively, the special additives may be contained in the applicator without zinc chloride. Transdermal applicators containing special pharmacologically active ingredients without zinc chloride may be utilized to enhance a previously applied zinc chloride mixture and hold it in place on the skin. For purposes of simplicity the contents of the transdermal applicators will be hereinafter referred to as the xe2x80x9czinc chloride mixturexe2x80x9d.
The applicator is generally comprised of a fluid impermeable backing and the zinc chloride mixture adjoining the backing. Preferably, the applicator includes an adhesive substrate disposed on the backing so that the applicator can be adhered to the skin site.
In its most simple form, the applicator includes an adhesive substrate impregnated with the zinc chloride mixture layered between the backing and a liquid impermeable peel away strip temporarily positioned along one side of the backing.
In a more complex form, the applicator includes the fluid impermeable backing, an adhesive substrate disposed on the backing so that the applicator can be adhered to the skin site, and a secondary backing substrate flexibly affixed to the backing to form a reservoir for the zinc chloride mixture between the secondary backing and the peel away strip. The secondary backing typically includes a flange intended to prevent the zinc chloride mixture from seeping out from the intended skin site.
In another form, the transdermal applicator includes the fluid impermeable backing, an adhesive substrate disposed on the backing so that the applicator can be adhered to the skin site, and a polymer drug matrix impregnated with the zinc chloride mixture disposed between the backing and the peel away strip.
In yet another form, the transdermal applicator includes the fluid impermeable backing, an adhesive substrate disposed on the backing so that the applicator can be adhered to the skin site, and a rate controlling membrane disposed between the zinc chloride mixture and the peel away strip to control the rate at which the zinc chloride is administered.
Other features and advantages of the present invention will become apparent from the following more detailed description, taken in conjunction with the accompanying drawings which illustrate, by way of example, the principles of the invention.